4X6H

Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.00 Å
  • R-Value Free: 0.166 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.155 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors.

Borisek, J.Vizovisek, M.Sosnowski, P.Turk, B.Turk, D.Mohar, B.Novic, M.

(2015) J Med Chem 58: 6928-6937

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00746
  • Primary Citation of Related Structures:  
    4X6H, 4X6I, 4X6J

  • PubMed Abstract: 

    Cathepsin K is a major drug target for osteoporosis and related-bone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was developed. In order to avoid previous problems of cathepsin K inhibitors associated with lysosomotropism of compounds with basic character that resulted in off-target effects, a weakly- to nonbasic moiety was incorporated into the P3 position. Compounds 5, 6, and 9 were highly selective for cathepsin K when compared with cathepsins L and S, with the Ki values in the 10-30 nM range. The kinetic studies revealed that the new compounds exhibited reversible tight binding to cathepsin K, while the X-ray structural studies showed covalent and noncovalent binding between the nitrile group and the catalytic cysteine (Cys25) site.


  • Organizational Affiliation

    National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cathepsin K215Homo sapiensMutation(s): 0 
Gene Names: CTSKCTSOCTSO2
EC: 3.4.22.38
UniProt & NIH Common Fund Data Resources
Find proteins for P43235 (Homo sapiens)
Explore P43235 
Go to UniProtKB:  P43235
PHAROS:  P43235
GTEx:  ENSG00000143387 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP43235
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3XT
Query on 3XT

Download Ideal Coordinates CCD File 
B [auth A]4-amino-3-fluoro-N-(1-{[(2Z)-2-iminoethyl]carbamoyl}cyclohexyl)benzamide
C16 H21 F N4 O2
ULJOBOHEOALILQ-LSCVHKIXSA-N
I37
Query on I37

Download Ideal Coordinates CCD File 
C [auth A]4-amino-N-{1-[(cyanomethyl)carbamoyl]cyclohexyl}-3-fluorobenzamide
C16 H19 F N4 O2
NEJGUCSKQVFSJQ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
I37 Binding MOAD:  4X6H Ki: 22 (nM) from 1 assay(s)
BindingDB:  4X6H Ki: 22 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.00 Å
  • R-Value Free: 0.166 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.155 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 36.439α = 90
b = 54.551β = 90
c = 88.015γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PHASERphasing
PDB_EXTRACTdata extraction
SCALEPACKdata scaling
PROTEUM PLUSdata reduction
PROTEUM PLUSdata reduction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-09-23
    Type: Initial release
  • Version 1.1: 2024-01-10
    Changes: Data collection, Database references, Refinement description